Tetracyclic phenanthro furan heterocyclic derivatives compositions and use

ABSTRACT

The present invention relates to antitumor compounds of formula (I) 
     
         ArCH.sub.2 R.sup.1                                         (I) 
    
     or a monomethyl or monoethyl ether thereof (the compound of formula (I) including these ethers may contain no more than 29 carbon atoms in total); ethers, esters thereof; acid addition salts thereof; wherein Ar is a fused tetracyclic aromatic ring system comprised of 5-membered and 6-membered rings and contains at least one heteroatom and 3 aromatic rings and a total of no more than 18 ring atoms, or a substituted derivative thereof; the heteroatom is preferably oxygen, sulfur or nitrogen; when it is nitrogen this is substituted by hydrogen, methyl or ethyl; 
     R 1  contains not more than eight carbon atoms and is a group ##STR1## wherein m is O or 1; 
     R 5  is hydrogen; 
     R 6  and R 7  are the same or different and each is hydrogen or C 1-5  alkyl optionally substituted by hydroxy; 
     R 8  and R 9  are the same or different and each is hydrogen or C 1-3  alkyl; 
     --C--C-- is a five or six-membered saturated carbocyclic ring; 
     R 10  is hydrogen, methyl or hydroxymethyl; 
     R 11 , R 12  and R 13  are the same or different and each is hydrogen or methyl; 
     R 14  is hydrogen, methyl, hydroxy, or hydroxymethyl.

This is a division of Ser. No. 128,638, filed on Dec. 4, 1987now U.S.Pat. No. 4,797,497, which is a continuation-in-part of Ser. No. 673,356,filed Nov. 20, 1989, now abandoned.

The present invention relates to heteropolycyclic aromatic alkanolderivatives which have been found to have biocidal activity. Morespecifically the invention concerns aminoalkanol derivatives containinga heteropolycyclic aromatic ring system, methods for the synthesisthereof, novel intermediates therefor, pharmaceutical formulationsthereof and the use thereof as biocidal agents, particularly antitumoragents.

Accordingly, in a first aspect, the present invention provides acompound of the formula (I)

    ArCH.sub.2 R.sup.1                                         (I)

or a monomethyl or monoethyl ether thereof (the compound of formula (I)including these ethers may contain no more than 29 carbon atoms intotal); ethers, esters thereof; acid addition salts thereof; wherein Aris a fused tetracyclic aromatic ring system comprised of 5-membered and6-membered rings and contains at least one heteroatom and 3 aromaticrings and a total of no more than 18 ring atoms, or a substitutedderivative thereof; the heteroatom is preferably oxygen, sulfur ornitrogen; when it is nitrogen this is substituted by hydrogen, methyl orethyl; the ring system is optionally substituted by one or twosubstituents; preferably the ring system is unsubstituted or mono-substituted (the substituents will contain not more than four carbonatoms in total when taken together being the same or different and areselected from halogen; cyano; C₁₋₄ alkyl or C₁₋₄ alkoxy, each optionallysubstituted by hydroxy or C₁₋₂ alkoxy; halogen substituted C₁₋₂ alkyl orC₁₋₂ alkoxy; a group S(O)_(n) R² wherein n is an integer 0, 1 or 2 andR² is C₁₋₂ alkyl optionally substituted by hydroxy or C₁₋₂ alkoxy; orthe ring system is optionally substituted by a group NR³ R⁴ containingnot more than 5 carbon atoms wherein R³ and R⁴ are the same or differentand each is a C₁₋₃ alkyl group or NR³ R⁴ forms a five- or six-memberedheterocyclic ring optionally containing one or two additionalheteroatoms);

R¹ contains not more than eight carbon atoms and is a group ##STR2##wherein m is 0 or 1;

R⁵ is hydrogen;

R⁶ and R⁷ are the same or different and each is hydrogen or C₁₋₅ alkyloptionally substituted by hydroxy;

R⁸ and R⁹ are the same or different and each is hydrogen or C₁₋₃ alkyl;

--C--C-- is a five- or six-membered saturated carbocyclic ring;

R¹⁰ is hydrogen, methyl or hydroxymethyl;

R¹¹, R¹² and R¹³ are the same or different and each is hydrogen ormethyl;

R¹⁴ is hydrogen, methyl, hydroxy, or hydroxymethyl.

Specific ring systems included within the scope of the present inventioninclude; ##STR3## wherein Z is a heteroatom.

Suitably ArCH₂ R¹ or a monomethyl or monethyl either thereof containsnot more than 28 carbon atoms in total.

Suitably

Ar is ##STR4## wherein Z is O, S, NH, NCH₃, or NEt.

More suitably

Ar is ##STR5## wherein Z=O, S, NH, NCH₃ or NEt;

suitably

R¹ is ##STR6## wherein R¹⁶ is CH₂ OH, CH(CH₃)OH or CH₂ CH₂ OH,

R¹⁷ is hydrogen, C₁₋₃ alkyl or CH₂ OH,

R¹⁸ is hydrogen or methyl.

Preferably Ar is ##STR7## wherein Z=O, S, NH, NCH₃, NEt.

Most preferably Ar is ##STR8## preferably R¹⁶ is CH₂ OH or CH(CH₃)OH;R¹⁷ is hydrogen, methyl, ethyl or CH₂ OH.

Most preferably R¹ is a diol of the structure ##STR9## wherein R¹⁹ ishydrogen or methyl and R²⁰ is hydrogen, methyl or ethyl, preferablymethyl.

Acid addition-salts included within the scope of the present inventionare those of compound of formula (I) and ethers and esters thereof.

Esters and nonpharmaceutically useful salts of the compounds of theformula (I) are useful intermediates in the preparation and purificationof compounds of the formula (I) and pharmaceutically useful acidaddition salts thereof, and are therefore within the scope of thepresent invention. Thus, acid addition salts of the compounds of theformula (I) useful in the present invention include but are not limitedto those derived from inorganic acids, such as hydrochloric,hydrobromic, sulfuric and phosphoric acids, organic acids such asisethionic (2-hydroxyethylsulfonic), maleic, malonic, succinic,salicylic, tartaric, lactic, citric, formic, lactobionic, pantothenic,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,naphthalene-2-sulfonic, and ascorbic acids, and amino acids such asglycine.

Acid addition salts particularly useful as biocidal agents are thosethat are pharmacologically and pharmaceutically acceptable. Thus,suitable acid addition salts include but are not limited to thosederived from hydrochloric, methanesulfonic, ethanesulfonic, isethionic,lactic, and citric acids.

The preferred pharmacologically and pharmaceutically acceptable saltsare those that are soluble in solvents suitable for parenteraladministration, for example, hydrochlorides, methanesulfonates andisethionates.

Esters of compounds of formula (I) are derived from acids known to thoseskilled in the art to be suitable for ester formation, and areconveniently those derived from C₁₋₆ alkanoic acids or alkanoic acidderivatives, for example acetic acid, propionic acid, n-butyric acid andiso-butyric acid. The esters may be formed from all or only some of thehydroxy groups contained in the compounds of formula (I). Specificcompounds within the scope of formula (I) include;

2-[(Benzo[b]naphtho[2,1-d]thiophen-5-ylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(Benzo[b]naphtho[2,3-d]furan-6-ylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(Benzo[b]naphtho[1,2-d]furan-5-ylmethyl)amino]-2-methyl-1,3-propanediol,

2-Methyl-2-[[(7-methyl-7H-benzo[c]carbazol-10-yl)methyl]amino]-1,3-propanediol,

2-[(Benzo[b]napahtho[2,1-d]furan-5-ylmethyl)amino]-2-methyl-1,3-propanediol

2-Methyl-2-[(phenanthro[1,2-b]furan-11-ylmethyl)amino]-1,3-propanediol,

2-Methyl-2-[(phenanthro[1,2-b]thiophen-2-ylmelthyl)amino]-1,3-propanediol,

2-Methyl-2-[(phenanthro[1,2-b]thiophen-11-ylmethyl)amino]-1,3-propanediol,

2-Methyl-2-[(phenanthro[4,3-b]furan-2-ylmethyl)amino]-1,3-propanediol,

2-Methyl-2-[(phenanthro[4,3-b]thiophen-7-ylmethyl)amino]-1,3-propanediol,

2-Methyl-2-[(phenanthro[9,10-b]furan-2-ylmethyl)amino]-1,3-propanediol,

2-Methyl-2[(phenanthro[9,10-c]thiophen-1-ylmethyl)amino]-1,3-propanediol,

2-[Acenaphtho-[1,2-b]thiophen-8-ylmethyl)amino]-2-methyl-1,3-propanediol,

2-[Acenaptho-[1,2-c]thiophen-7-ylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(Benzo[b]naphtho[2,3-d]furan-7-ylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(Benzo[b]naphtho[2,3-d]thiophen-6-ylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(Benzo[b]naphtho[2,3-d]thiophen-8-yl-methyl)amino]-2-methyl-1,3-propanediol,

2-[(Benzo[b]naphtho[2,3-d]thiophen-7-ylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(Benzo[b]naphtho[2,3-d]furan-11-ylmethyl)amino[-2-methyl-1,3-propanediol

2-[(5-Ethyl-5H-benzo[b]carbazol-7-yl)methyl]amino]-2-methyl-1,3-propanediol

2-[[(5-Ethyl-5H-benzo[b]carbazol-6-yl)methyl]amino]-2-methyl-1,3-propanediol,

2-[(Benzo[b]naphtho[1,2-d]thiophen-5-ylmethyl)amino]-2-methyl-1,3-propanedioland

2-Methyl-2-[(phenanthro[1,2-b]furan-2-ylmethyl)amino]-1,3-propanediol;

ethers, esters thereof; acid addition salts thereof.

Of these specific examples of compounds of formula (I), the mostpreferred compounds are2-methyl-2-[[(7-methyl-7H-benzo[c]carbazol-10-yl)methyl]amino]1,3-propanedioland2-[(benzo[b]naphtho[2,1-d]furan-5-ylmethyl)amino]2-methyl-1,3-propanediol;ethers, esters thereof; acid addition salts thereof.

The compounds of formula (I) and their ethers, esters and salts thereofmay be prepared by any method known in the art for the preparation ofcompounds of analogous structure. Thus, the compounds of formula (I)may, for example, be prepared by any of the methods defined below. 1.The reduction of a compound of formula (II) ##STR10## Wherein R² -R⁴ andR⁶ -R¹⁴ are as hereinbefore defined or a suitably protected derivativethereof followed by deprotection where appropriate.

The conditions and reagents for such a reaction are well known to thoseskilled in the art, and any such conditions/reagents may be employed.The conversion of (II) or suitably protected derivatives thereof may becarried out by a reducing agent followed by deprotection if necessary.The reduction is conveniently carried out by a metal hydride such aslithium aluminum hydride, sodium borohydride, sodium cyanoborohydride,or by catalytic hydrogenation, conveniently by hydrogen in the presenceof a metal catalyst such as palladium or platinum, or equivalentreagents as outlined by J. March, Advanced Organic Chemistry, 2nd ed.,pages 819-820, McGraw Hill, New York, 1977. The reduction is suitablycarried out with the compound of formula (II) in solution in an inertsolvent or mixture of solvents compatible with the reducing agent, at anon-extreme temperature, for example, between 0° and 80° C.,conveniently at room temperature.

In the case of lithium aluminum hydride and like reagents, suitablesolvents include ethers (for example tetrahydrofuran, diethyl ether and1,2-dimethoxyethane) optionally in the presence of a hydrocarboncosolvent (for example toluene, benzene or hexane).

In the case of sodium borohydride and like reagents, suitable solventsinclude alcohols (for example ethanol, methanol or isopropanol)optionally in the presence of a hydrocarbon cosolvent (for exampletoluene, benzene or hexane) or an ether cosolvent (for example diethylether or tetrahydrofuran).

In the case of sodium cyanoborohydride and like reagents, suitablesolvents include those described for sodium borohydride and in thepresence of an acid conveniently glacial acetic acid or ethanolichydrochloric acid as outlined in, for example, R. Hutchins et al.,Organic Preparations and Procedures International 11, 201 (1979).

In the case of catalytic hydrogenation, suitable solvents includealcohols (for example methanol and ethanol) optionally in the presenceof a hydrocarbon cosolvent (for example toluene or benzene) or ethercosolvent (for example diethyl ether or tetrahydrofuran) in the presenceof an acid (for example glacial acetic acid or ethanolic hydrochloricacid) or in glacial acetic acid.

Protected derivatives of compounds of formula (II) are conveniently usedwhen lithium aluminum hydride is employed as the reducing agent.Convenient protecting groups are compatible with the reducing agentutilized and are readily removed under nondestructive conditions, forexample benzyl, tetrahydropyranyl and isopropylidene ethers.

It is often convenient not to isolate the compound of the formula (II)but to react a compound of the formula (III) with a compound of theformula (IV): ##STR11## wherein Ar and R² -R⁴ and R⁶ -R¹⁴ are as definedin (I), and reduce the compound of the formula (II) so formed in situ.The reaction of the compounds of the formulae (III) and (IV) is againsuitably carried out using conditions and reagents which are well knownto those skilled in the art, for example in the presence of an acid,such as a sulfonic acid, i.e., p-toluenesulfonic acid, in an appropriateinert solvent, such as an aromatic hydrocarbon, suitably toluene, withazeotropic removal of water followed by treatment with the reducingagent in an appropriate solvent, suitably ethanol or methanol.Alternatively, (II) formed under equilibrium conditions in appropriatesolvents can be reduced in situ with an appropriate reducing agent,suitably sodium cyanoborohydride. The compound of formula (III) may bein the form of a protected aldehyde, for example an acetal, whichliberates the aldehyde function under the reaction conditions.

In turn, a compound of formula (III) can be synthesized by reacting theappropriate aromatic heteropolycycle with a formylating agent such asthat generated by the reaction between SnCl₄ and Cl₂ CHOCH₃ orequivalent reagents, for example, according to the method of A. Riecheet al., Chem. Ber. 93, 88 (1960), or with other standard formylatingreagents/procedures known to the art, for example, the Gatterman-Kochreaction reaction (CO/HCl/AlCl₃ /CuCl), the Gatterman reaction(HCN/HCl/ZnCl₂), and the Vilsmeier reaction (POCl₃ /PhN(Me)CHO, or POCl₃/Me₂ NCHO) (J. March, vide supra, pages 494-497).

The compounds of the formula (III) may also be prepared from anappropriate aromatic heteropolycycle substituted by a suitablefunctional group such as (but not limited to) esters, CH₂ OH, CHBr₂,CH₃, COCH₃, COOH, or CN, and converting this functional group to analdehyde group by methods well known to those skilled in the art.

Where the aromatic heteropolycycle bears substituents, the compound offormula (III) may be prepared by a variety of methods known in the artof organic chemistry depending on the nature of the substituent on theheteropolycyclic ring. For example, if the substituent(s) is a halogen,the starting materials may be prepared by direct treatment of thearomatic heteropolycycle with a halogenating agent (e.g., Cl₂, Br₂, orSO₂ Cl₂) or indirectly by such routes as the Sandmeyer reaction (H. H.Hodgson, Chem. Rev. 40, 251 (1947). If the substituent(s) is alkyl, thearomatic heteropolycycle may be reacted with the appropriate reagentsunder Friedel-Crafts reaction conditions (G. A. Olah, Friedel Crafts andRelated Reactions, Vols. 1-3, Interscience, New York, N.Y., 1963-1965).

In appropriate cases, the compounds of the formula (IV) and ethersthereof also may be prepared by methods known in the art, for example,by the reaction of a compound of the formula (V) ##STR12## (or ethersthereof) wherein R⁷ -R⁹ and R¹¹ -R¹⁴ and m are as hereinbefore definedwith an appropriate aldehyde, conveniently acetaldehyde or formaldehyde(as in B. M. Vanderbilt and H. B. Hass, Ind. Eng. Chem. 32, 34 (1940))followed by reduction (as outlined in J. March, vide supra, pages1125-1126), conveniently by hydrogen and a metal catalyst (for example,a platinum containing catalyst) in an appropriate solvent, convenientlyglacial acetic acid.

2. The reduction of a compound of the formula (VI) ##STR13## wherein Arand R² -R¹⁴ are as hereinbefore defined and the hydroxy groups areoptionally protected, followed by deprotection of the hydroxy groupswhere appropriate. The reduction may be carried out by standard reducingagents known for carrying out this type of reduction (as outlined in J.March, vide supra page 1122), for example, a hydride reagent such aslithium aluminium hydride in an inert solvent, such as an ether, i.e.tetrahydrofuran, at a non-extreme temperature, for example, at between0° and 100° C. and conveniently at the reflux temperature of the ether.To compound of the formula (VI) may be formed by the reaction of theappropriate acid (ArCOOH) or a suitable reactive acid derivative thereof(as outlined in J. March, vide supra, pages 382-390), for example, anacid halide, in an inert solvent with an amine of the formula (IV) inwhich the hydroxy groups are optionally protected, for example, when thecompound of the formula (IV) is a diol, by an isopropylidene group. Thecompound of the formula (VI) so formed is suitably reduced in situ anddeprotected if necessary to give a compound of formula (I). Thecompounds of the formula ArCOOH can be prepared by methods well known tothose skilled in the art. 3. The reaction of a compound ArCH₂ L (whereinAr is as hereinbefore defined and L is a leaving group) with a compoundof the formula (IV) as hereinbefore defined. Suitable leaving groups arethose defined by J. March, vide supra, pages 325-331, and includehalogens such as chlorine and bromine and sulfonic acid derivatives suchas p-toluenesulfonate. The reaction is suitably carried out in anappropriate solvent, such as a dipolar aprotic solvent or alcohol at anon-extreme temperature, for example 50°-100°. The compounds of theformula ArCH₂ L can be prepared by methods well known to those skilledin the art.

There is therefore provided, as a further aspect of the invention, amethod for the preparation of a compound of formula (I) comprising anymethod known for the preparation of analogous compounds, in particularthose methods defined in (1) to (3) hereinabove.

The compounds of this invention have biocidal activity, e.g., are toxicto certain living cells which are detrimental to mammals, for examplepathogenic organisms and tumor cells. While the compounds herein havebiocidal activity, it should be appreciated that the range and level ofactivity may vary from compound to compound, and therefore the compoundsare not necessarily equivalent.

This toxicity to pathogenic organisms has been demonstrated by activityagainst viruses (e.g., Herpes simplex 1/vero), fungi (e.g., Candidaalbicans), protozoa (e.g., Eimeria tenella and Trichomonas vaginalis),bacteria (e.g., Mycoplasma smegmatis and Strepotococcus pyogenes), andhelminths (e.g., Nippostrongylus brasiliensis). The antitumor activityof compounds of formula (I) has been demonstrated in a number ofrecognized screens and primarily by activity against ascitic P388/0leukemia.

Preferred compounds of the formula (I) are those which have antitumoractivity. The activity against ascitic tumors, including P388/0, isevidenced by reduction of tumor cell number in mammals (for example,mice bearing ascitic tumors) and consequent increase in survivalduration as compared to an untreated tumor-bearing control group.Antitumor activity is further evidenced by measurable reduction in thesize of solid tumors following treatment of mammals with the compoundsof this invention compared to the tumors of untreated controltumor-bearing animals. Compounds of formula (I) are active againstmurine tumors such as lymphocytic leukemia P388/0, lymphocytic leukemiaL1210, melanotic melanoma B16, P815 mastocytoma, MDAY/D2 fibrosarcoma,colon 38 adenocarcinoma, M5076 rhabdomyosarcoma and Lewis lungcarcinoma.

Activity in one or more of these tumor tests has been reported to beindicative of antitumor activity in man (A. Goldin et al., in Methods inCancer Research ed. V. T. DeVita Jr. and H. Busch, 16 165, AcademicPress, N.Y. 1979).

There are sublines of P388/0 which have been made resistant to thefollowing clinically useful agents: cytosine arabinoside, doxorubicin,cyclophosphamide, L-phenylalanine mustard, methotrexate, 5-fluorouracil,actinomycin D, cis-platin and bis-chloroethylnitrosourea. Compounds ofthis invention show potent activity against these drug-resistant tumorsusing the procedures for P388/0 above.

Compounds of formula (I) have also been found to be active against humantumor cells in primary cultures of lung, ovary, breast, renal, melanoma,unknown primary, gastric, pancreatic, mesothelioma, myeloma, and coloncancer. As used herein "cancer " is to be taken as synonymous with"malignant tumor" or more generally "tumor" unless otherwise noted. Thisis a procedure in which the prevention of tumor cell colony formation,i.e., tumor cell replication, by a drug has been shown to correlate withclinical antitumor activity in man (D. D. Von Hoff et al., CancerChemotherapy and Pharmacology 6, 265 (1980); S. Salmon and D. D. VonHoff, Seminars in Oncology, 8, 377 (1981)).

Compounds of formula I which have been found to have antitumor activityintercalate in vitro with DNA (this property is determined byviscometric methods using the procedure of W. D. Wilson et al., NucleicAcids Research 4, 2697 (1954)) and a log P as calculated by the methodof C. Hansch and A. Leo in Substituent Constants for CorrelationAnalysis in Chemistry and Biology, John Wiley and Sons, New York, 1979,lying in the range between -2.0 and +2.5.

As has been described above, the compounds of the present invention areuseful for the treatment of animals (including humans) bearingsusceptible tumors. The invention thus further provides a method for thetreatment of tumors in animals, including mammals, especially humans,which comprises the administration of a clinically useful amount ofcompound of formula (I) in a pharmaceutically useful form, once orseveral times a day or other appropriate schedule, orally, rectally,parenterally, or applied topically.

In addition, there is provided as a further, or alternative, aspect ofthe invention, a compound of formula (I) for use in therapy, for exampleas an antitumor agent.

The amount of compound of formula (I) required to be effective as abiocidal agent will, of course, vary and is ultimately at the discretionof the medical or veterinary practitioner. The factors to be consideredinclude the condition being treated, the route of administration, thenature of the formulation, the mammal's body weight, surface area, ageand general condition, and the particular compound to be administered. Asuitable effective antitumor dose is in the range of about 0.1 to about120 mg/kg body weight, preferably in the range of about 1.5 to 50 mg/kg,for example 10 to 30 mg/kg. The total daily dose may be given as asingle dose, multiple doses, e.g., two to six times per day, or byintravenous infusion for a selected duration. For example, for a 75 kgmammal, the dose range would be about 8 to 9000 mg per day, and atypical dose would be about 2000 mg per day. If discrete multiple dosesare indicated, treatment might typically be 500 mg of a compound offormula (I) given 4 times per day in a pharmaceutically usefulformulation.

While it is possible for the active compound (defined herein as compoundof formula (I), or ether, ester, or salt thereof) to be administeredalone, it is preferable to present the active compound in apharmaceutical formulation. Formulations of the present invention, formedical use, comprise an active compound together with one or morepharmaceutically acceptable carriers thereof and optionally othertherapeutical ingredients. The carrier(s) must be pharmaceuticallyacceptable in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

The present invention, therefore, further provides a pharmaceuticalformulation comprising a compound of formula (I) (in the form of thefree base, ether, or ester derivative or a pharmaceutically acceptableacid addition salt thereof) together with a pharmaceutically acceptablecarrier therefor.

There is also provided a method for the preparation of a pharmaceuticalformulation comprising bringing into association a compound of formula(I), an ether, ester, or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier therefor.

While the antitumor activity of the compounds of formula (I) is believedto reside in the free base, it is often convenient to administer an acidaddition salt of a compound of formula (I):

The formulations include those suitable for oral, rectal or parenteral(including subcutaneous, intramuscular and intravenous) administration.Preferred are those suitable for oral or parenteral administration.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active compound intoassociation with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active compound into assocation with a liquidcarrier or a finely divided solid carrier or both and then, ifnecessary, shaping the product into desired formulations.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a suspension in an aqueous liquid ornon-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active compound in a free-flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine, a mixture of thepowdered active compound with any suitable carrier.

A syrup may be made by adding the active compound to a concentrated,aqueous solution of a sugar, for example sucrose, to which may also beadded any accessory ingredients. Such accessory ingredient(s) mayinclude flavorings, an agent to retard crystallization of the sugar oran agent to increase the solubility of any other ingredient, such as apolyhydric alcohol for example glycerol or sorbitol.

Formulations for rectal administration may be presented as a suppositorywith a conventional carrier such as cocoa butter.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the active compound which ispreferably isotonic with the blood of the recipient. Such formulationssuitably comprise a solution of a pharmaceutically and pharmacologicallyacceptable acid addition salt of a compound of the formula (I) that isisotonic with the blood of the recipient. Thus, such formulations mayconveniently contain distilled water, 5% dextrose in distilled water orsaline and a pharmaceutically and pharmacologically acceptable acidaddition salt of a compound of the formula (I) that has an appropriatesolubility in these solvents, for example the hydrochloride, isethionateand methanesulfonate salts, preferably the latter.

Useful formulations also comprise concentrated solutions or solidscontaining the compound of formula (I) which upon dilution with anappropriate solvent give a solution suitable for parental administrationabove.

In addition to the aforementioned ingredients, the formulations of thisinvention may further include one or more accessory ingredient(s)selected from diluents, buffers, flavoring agents, binders, surfaceactive agents, thickeners, lubricants, preservatives (includingantioxidants) and the like.

The following examples are provided by the way of illustration of thepresent invention and should in no way be construed as a limitationthereof.

General Comments

All solvents were reagent grade and used without further purificationwith the following exceptions. THF was dried by distillation from Na/Kalloy under nitrogen (N₂) and used immediately. Toluene (PhCH₃) wasdistilled from CaH₂ under N₂ and stored over 3Å molecular sieves.Chemicals used were reagent grade and used without purification unlessnoted. The full name and address of the suppliers of the reagents andchemicals is given when first cited. After this, an abbreviated name isused.

Preparative HPLC was carried out on a Water's Prep LC/System 500Amachine using two 500 g silica gel (SiO₂) cartridges unless otherwisenoted. Plugs of SiO₂ used for purifications were "flash chromatography"SiO₂ (Merck & Co., Inc., Merck Chemical Division, Rahway, N.J. 07065,Silica Gel 60, 230-400 mesh). In this procedure, an appropriate volumesintered glass funnel was filled approximately 3/4 full with the SiO₂and packed evenly by tapping the outside of the funnel. A piece offilter paper was then placed on top of the SiO₂ and a solution of thematerial to be purified applied evenly to the top. Gently suctionthrough a filter flask moved the eluting solvent through the plugrapidly. The appropriate size fractions were combined as needed andfurther manipulated.

General procedures are described in detail. Analogous procedures showmelting point (mp), recrystallization solvents, and elemental analyses(all elements analyzing within a difference of ≦0.4% of the expectedvalue). Any changes to the procedure such as solvent, reactiontemperature, reaction time, or workup are noted. NMR (¹ H, ¹³ C), and MSdata of all new products were consistent with the expected and proposedstructures. The positions assigned to structural isomers wereunequivocally determined by a number of NMR techniques. All finalproducts were dried in a vacuum oven at 20 mm Hg pressure at thetemperature indicated overnight (12-16 h). All temperatures are indegrees Celsius. Other abbreviations used are: room temperature (RT),absolute (abs.), round bottom flask (RB flask), minutes (min), hours(h).

EXAMPLE 12-[(Benzo[b]naphtho[2,1-d]thiophen-5-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate

To a 3-necked RB flask equipped with magnetic stirring bar, condenser,thermometer, Dean-Stark trap, and N₂ inlet line with bubbler was addedbenzo[b]naphtho[2,1-d]thiophene-5-carbaldehyde (H. G. ParsPharmaceutical Laboratories, Inc., 763 Concord Avenue, Cambridge, MA02138, 4.94 g, 18.83 mmol), 2-amino-2-methyl-1,3-propanediol (AldrichChemical Co, P. O. Box 2060, Milwaukee, WI 53201, 1.98 g, 18.83 mmol),p-toluenesulfonic acid monohydrate (Aldrich, 0.1 g) and PhCH₃ (200 mL).The mixture was stirred at reflux with removal of H₂ O for 2.5 h (oruntil no H₂ O is collected). Most of the PhCH₃ was then removed bydistillation. The mixture was then cooled in an ice bath and dilutedwith abs. EtOH (200 mL) and further cooled. Solid NaBH₄ (MCBManufacturing Chemists, Inc., 2909 Highland Ave., Cincinnati, OH 45212,0.712 g, 18.83 mmol) was added in one portion to the reaction mixture.The ice bath was then removed, the reaction mixture allowed to warm toRT and stirred overnight. The reaction was then acidified with 10% HCland the solvents removed by rotary evaporation. The crude solid wasshaken with 1N HCl (300 mL) filtered, washed with 1N HCl (300 mL),sucked semidry, and washed with Et₂ O (300 mL). The material wasdissolved in CH₃ OH (200 mL), filtered and basified with 1N NaOHsolution (1 L). A white solid formed which was extracted with EtOAc(3×500 mL). The EtOAc washings were combined, filtered, washed withsaturated NaCl (3×500 mL), dried (K₂ CO₃), filtered and concentrated byrotary evaporation to give a white solid. This was dissolved in amixture of abs. EtOH (200 mL) and CH₃ SO₃ H (99.5%, Morton Thiokol,Inc. - Alfa Products, P. O. Box 299, 152 Andover Street, Danvers, MA01923, 3 mL), filtered and diluted to 4 L with a mixture of Et₂ O/hexane(1:1). This material was then recrystallized (EtOH/hexane, 1:3) to give2-[(benxo-[b]naphtho[2,1-d]thiophen-5-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate, mp 221°-222° (C,H,N,S).

Alternatively, the crude reaction mixture could be treated with 1N NaOHsolution or H₂ O before the solvents were removed. After thoroughwashing with H₂ O and drying the resulting crude solid converted to itsacid addition salt with either ethanolic HCl or methanesulfonic acid.Recrystallization of the resulting salt can be accomplished usingi-PrOH, CH₃ OH, EtOH or other alcohols alone or in combination with anonpolar solvent such as Et₂ O, hexane, PhCH₃ or other inert solvents.

EXAMPLE 22-[(Benzo[b]naphtho[2,3-d]furan-6-ylmethyl)amino]-2-methyl-1,3-propanediol2A. Benzo[b]naphtho[2,3-d]furan-6-carbaldehyde 2B.Benzo[b]naphtho[2,3-d]furan-11-carbaldehyde

Benzo[b]naphtho[2,3-d]furan (H. G. Pars Pharmaceutical Laboratories,Inc.) was formylated using the procedure of A. Rieche et al., Chem. Ber.93, 88 (1960). The crude aldehyde appeared to be mainly one isomeraccompanied by a small amount of a second aldehyde by TLC. Purificationby chromatography (SIO₂, PhCH₃) followed by recrystallization (CH₂ Cl₂/hexane) gave the main component in 58% yield identified using NMRtechniques to be benzo[b]naphtho[2,3-d]furan 6-carbaldehyde, (2A) mp169°14 171.5°, (C,H). The minor component, obtained in 3.4% yield wasshown by NMR to be benzo[b]naphtho[2,3-d]furan-11-carbaldehyde, mp128°-132°, (C,H), (PhCH₃ /hexane).

2B. 2-[(Benzo[b]naphtho[2,3-d]furan-6-ylmethyl]-2-methyl-1,3-propanediolmethanesulfonate.0.4 H₂ O

Using the reductive amination procedure described in Example 1,benzo[b]naphtho[2,3-d]furan-6-carbaldehyde (2A) and2-amino-2-methyl1,3-propanediol (Aldrich) gave a 64.7% yield of2-[(benzo[b]naphtho[2,3-d]furan-6-ylmethyl)amino-2-methyl-1,3-propanediolmethanesulfonate. 0.4 H₂ O, mp 187°-190°, (C,H,N,S), (EtOH/Et₂ O).

EXAMPLE 32-[(Benzo[b]naphtho[1,2-d]furan-5-ylmethyl)amino]-2methyl-1,3-propanediol3A. Benzo[b]naphtho[1,2-d]furan-5-carbaldehyde

Benzo[b]naphtho[1,2-d]furan (H. G. Pars Pharmaceutical Laboratories,Inc.) was formylated using the procedure of A. Rieche et al., Chem. Ber.93, 88 (1960). The crude aldehyde appeared to be only one isomer by TLC.Purification by chromatography (SiO₂, PhCH₃) followed byrecrystallization (CH₂ Cl₂ /hexane) gave pure material (39% yield),identified using NMR techniques to bebenzo[b]naphtho[1,2-d]furan-5-carbaldehyde, mp 143°-145°, (C,H). 3B.2-[(Benzo[b]naphtho[1,2-d]furan-5-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate

Using the reductive amination procedure described in Example 1,benzo[b]naphtho[1,2-d]furan-5-carbaldehyde (3A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 72.1% yield of2-[(benzo[b]naphtho[1,2-d]furan-5-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate, mp 215°-217°, (C,H,N,S), (EtOH/Et₂ O).

EXAMPLE 42-Methyl-2-[[(7-methyl-7H-benzo[c]-carbazol-10-yl)methyl]amino]1,3-propanediol4A. 7-Methyl-7H-benzo[c]carbazole

To a RB flask equipped with magnetic stirring bar, reflux condenser andN₂ inlet line with bubbler was added 7H-benzo[c]carbazole (H. G. ParsPharmaceutical Laboratories, Inc., 6.6 g, 30.4 mmol) and dry THF (250mL). To the flask was added on one portion potassium t-butoxide(Aldrich, 4.2 g, 37.4 mmol). Dimethylsulfate (Aldrich, 7.56 g, 60.0mmol, 5.9 mL) was added dropwise to the solution and the mixture stirredfor 15 min. TLC (SiO₂ /PhCH₃) showed the reaction to be complete. Thereaction mixture was then poured into a 1N NaOH solution (2 L) andstirred. The white solid which formed was collected by filtration,washed with H₂ O (3×500 mL), sucked semidry, dissolved in PhCH₃ (300 mL)and eluted through a plug of SiO₂ (5×5 cm) using PhCH₃ as the elutingsolvent. Appropriate fractions were combined and the solvent removed togive a crude white product. This material was dissolved in CH₂ Cl₂ (400mL), filtered and diluted to 1 L with hexane. The mixture wasconcentrated to 500 mL by rotary evaporation. A white solid formed whichwas filtered, washed with pentane and dried in a vacuum to give 5.0 g of7-methyl-7H-benzo[c]carbazole, mp 116°-118°, (C,H,N). A further 1.06 gof product was obtained on standing and further concentration of thefiltrate to give a combined yield of 87.3%.

4B. 7-Methyl-7H-benzo[c]carbazole-10-carbaldehyde 4C.7-Methyl-7H-benzo[c]carbazole-5-carbaldehyde

7-Methyl-7H-benzo[c]carbazole (4A) was formylated using the procedure ofA. Rieche et al., Chem. Ber. 93, 88 (1960). TLC (SiO₂ /PhCH₃) showedthat the crude mixture contained two aldehydes. Column chromatography(SiO₂ /PhCH₃) followed by crystallization (CH₂ Cl₂ /pentane) gave eachof the aldehydes in isomerically pure form. A total of 3.83 g (59.1% ofthe more mobile main component,7-methyl-7H-benzo[c]carbazole-10-carbaldehyde, mp 164°-165°, (C,H,N). Atotal of 0.55 g (8%) of a minor, less mobile component was identified byNMR as 7-methyl-7H-benzo[c]carbazole-5-carbaldehyde, mp 210°-213°(C,H,N).

4D.2-Methyl-2-[[(7-methyl-7H-benzo[c]carbazol-10-yl)methyl]amino]1,3-propanediolhydrochloride.0.3 H₂ O

Using the procedure outlined in Example 1,7-methyl-7H-benzo[c]carbazole-10-carbaldehyde (4B) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave2-methyl-2-[[(7-methyl-7H-benzo[c]carbazol-10-yl)methyl]amino]-1,3-propanediolhydrochloride 0.3 H₂ O, mp 229°-230° (dec), (C,H,N,Cl), (EtOH/Et₂ O).

EXAMPLE 52-[((Benzo[b]naphtho[2,1-d]furan-5-ylmethyl)amino-2-methyl)1,3-propanediol5A. Benzo[b]naphtho[2,1-d]furan-5-carbaldehyde

Benzo[b]naphtho[2,1-d]furan (H. G. Pars Pharmaceutical Laboratories,Inc.) was formylated according to the procedure of A. Rieche et al.,Chem. Ber. 93, 88 (1960). The crude product appeared to contain only onealdehyde. The crude material was then purified by flush chromatographyon SiO₂ with CH₂ Cl₂ as the eluting solvent. The appropriate fractionswere combined and the solvent removed to give the crude material whichwas then recrystallized (CH₂ Cl₂ /hexane) to give a 78% yield ofbenzo[b]naphtho[2,1-d]furan-5-carbaldehyde, mp 123°-125°, (C,H).

5B.2-[(Benzo[b]naphtho[2,1-d]furan-5-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate

Using the procedure outlined in Example 1,benzo[b]naphtho(2,1-d]furan-5-carbaldehyde (5A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 59.2% yield of2-[(benzo[b]naphtho[2,1-b]furan-5-ylmethyl)amino]2-methyl-1,3-propanediolmethanesulfonate, mp 216°-218°, (C,H,N,S), EtOH/Et₂ O).

EXAMPLE 62-[(Benzo[b]naphtho[2,3-d]furan-7-ylmethyl)amino]-2-methyl-1,3-propanediol6A. 7-Bromomethyl-benzo[b]naphtho[2,3-d]furan

To a RB flask was added 7-methyl-benzo[b]naphtho-[2,3-d]furan (CambridgeChemicals, Inc., 16.0 g, 0.07 mol), N-bromosuccinimide (Aldrich 12.8 g,0.072 mol, recrystallized from H₂ O and dried under high vacuumovernight), a catalytic amount of benzoyl peroxide (0.01 g) and CCl₄ (1L). The mixture was refluxed for 2.5 h, cooled and filtered to removethe succinimide formed in the reaction. The solvent was then removedfrom the reaction mixture by rotary evaporation. The crude product waspurified by flush chromatography on SiO₂ using PhCH₃ as the elutingsolvent. The appropriate fractions were combined and the solvent onceagain removed by rotary evaporation to give 22.0 g of product. Thematerial (which was one spot by TLC and pure by NMR) was used withoutfurther purification.

6B.2-[(Benzo[b]naphtho[2,3-d]furan-7-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate.0.25 H₂ O

To a RB flask was added 7-bromomethyl-benzo[b]naphtho[2,3-d]furan (6A,22.0 g, 0.0706 mol), 2-methyl-2-amino-1,3-propanediol (Aldrich, 14.84 g,0.141 mol), K₂ CO₃ (Mallinckrodt, 19.49 g, 0.141 mol) and abs. ethanol(600 mL). The mixture was refluxed overnight, cooled and filtered. Thesolvent was then removed by rotary evaporation to give a white residue.This was shaken with hot H₂ O (500 mL). The mixture was allowed to standat RT for 1 h and the resulting solid filtered. The mixture was filteredand the resulting solid washed with warm H₂ O (2×500 mL). The damp solidwas dissolved in abs. EtOH (400 mL) containing methanesulfonic acid (3mL). The liquid was filtered through a fine fritted glass funnel and thefiltrate diluted to 2 L with Et₂ O. The resulting solid was filtered andrecrystallized (EtOH/Et₂ O, 1:2). After drying in a vacuum ovenovernight at 80° , 9.67 g (32% yield) of2-[(benzo[b]naphtho[2,3-d]furan-7-yl-methyl)amino]-2-methyl-1,3-propanediolmethanesulfonate.0.25 H₂ O, mp 248°-249° (dec), (C,H,N,S).

EXAMPLE 72-[(Benzo[b]naphtho[2,3-d]thiophen-6-ylmethyl)amino]-2methyl-1,3-propanediol7A. Benzo[b]naphtho[2,3-d]thiophene-6-carbaldehyde

Benzo[b]naphtho[2,3-d]thiophene (Cambridge Chemicals, Inc.) wasformylated using the procedure of A. Rieche et al., Chem. Ber 93, 88(1960), to give a 78% yield ofbenzo[b]naphtho[2,3-d]thiophene-6-carbaldehyde, mp 199°, (C,H,S), (CH₂Cl₂ /hexane).

7B.2-[(Benzo[b]naphtho[2,3-d]thiophen-6-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate

Using the procedure outlined in Example 1,benzo[b]naphtho[2,3-d]thiophene-6-carbaldehyde (7A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave 67.1% yield of2-[(benzo[b]naphtho[2,3-d]thiophen-6-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate, mp 242°-243°, (C,H,N,S), (EtOH/Et₂ O).

EXAMPLE 82-[(Benzo[b]naphtho[2,3-d]thiophen-8-ylmethyl)amino]2-methyl-1,3-propanediol8A. Benzo[b]naphtho[2,3-d]thiophene-8-carbaldehyde

To a RB flask equipped with magnetic stirring bar, reflux condenser andN₂ inlet line with bubbler was added2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (Aldrich, 38.6 g, 0.119mol), H₂ O (100 mL) and CHCl₃ (1500 mL). After refluxing the mixture for15 min, 8-methylbenzo[b]naphtho-[2,3-d]thiophene (Cambridge Chemicals,Inc., 21.0 g, 89.6 mmol) was added to the flask. After refluxing themixture for 5 h an additional portion of DDQ (19.3 g, 85 mmol) wasadded. The mixture was then refluxed overnight, cooled and the deep redsolution filtered. The solvent was then removed by rotary evaporationand the residual H₂ O removed by azeotropic distillation with severalportions of PhCH₃. The material was then dissolved in PhCH₃ (500 mL) andapplied to a 40×10 cm column of SiO₂ and eluted with additional PhCH₃ asthe solvent. The appropriate fractions were combined and the solventremoved to give 7.12 g of crude material. This was crystallized (PhCH₃),filtered and dried to give 5.35 g (22.7% yield) ofbenzo[b]naphtho[2,3-d]thiophene-8-carbaldehyde, mp 182°-185°, (C,H,S).

8B.2-[(Benzo[b]naphtho[2,3-d]thiophen-8-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate.0.6 H₂ O

Using the procedure outlined in Example 1,benzo[b]naphtho[2,3-d]thiophene-8-carbaldehyde (8A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 60.1% yield of2-[(benzo[b]naphtho[2,3-d]thiophen-8-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate.0.6 H₂ O, mp 245°-246° (dec), (C,H,N,S), (EtOH/Et₂ O).

EXAMPLE 92-[(Benzo[b]naphtho[2,3-d]thiophen-7-ylmethyl)amino]-2-methyl-1,3-propanediol9A. Benzo[b]naphtho[2,3-d]thiophene-7-carbaldehyde

Using the procedure described in Example 8,7-methylbenzo[b]-naphtho[2,3-d]thiophene (Cambridge Chemicals, Inc.)gave an 18.7% yield of benzo[b]naphtho[2,3-d]thiophene-7-carbaldehyde,mp 199°-200°, (C,H,S), (PhCH₃ /hexane).

9B.2-[(Benzo[b]naphtho[2,3-d]thiophen-7-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate.0.5 H₂ O

Using the procedure outlined in Example 1,benzo[b]naphtho[2,3-d]thiophene-7-carbaldehyde (9A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 75.8% yield of2-[(benzo[b]naphtho[2,3-d]thiophen-7-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate.0.5 H₂ O, mp 210°-211° (dec), (C,H,N,S), (EtOH/Et₂ O).

EXAMPLE 102-[(Benzo[b]naphtho[2,3-d]furan-11-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate

Using the procedure outlined in Example 1,benzo[b]naphtho[2,3-d]-furan-11-carbaldehyde (2B) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 68.8% yield of2-[(benzo[b]naphtho[2,3-d]furan-11-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate, mp 219°-220° (dec), (C,H,N,S), (EtOH/Et₂ O).

EXAMPLE 112-[(5-Ethyl-5H-benzo[b]carbazol-7-yl)methy]amino]-2-methyl-1,3-propanediol11A. 5-Ethyl-5H-benzo[b]carbazole-7-carbaldehyde

Using the procedure outlined in Example 8A,5-ethyl-7-methyl-5H-benzo[b]carbazole (Cambridge Chemicals, Inc.) gave a15.4% 5-ethyl-5H-benzo[b]carbazole-7-carbaldehyde, mp 130°-133°,(C,H,N), (PhCH₃).

11B.2-[(5-Ethyl-5H-benzo[b]carbazol-7-yl)methy]amino]-2-methyl-1,3-propanediolmethanesulfonate

Using the procedure outlined in Example 1,5-ethyl-5H-benzo[b]carbazole-7-carbaldehyde (11A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 40.2% yield of2-[(5-ethyl-5H-benzo[b]carbazol-7-yl)methy]amino]2-methyl-1,3-propanediolmethanesulfonate, mp 219°-220° (dec), (C,H,N,S), (EtOH/Et₂ O).

EXAMPLE 122-[(5-Ethyl-5H-benzo[b]carbazol-6-yl)methy]amino]2-methyl-1,3-propanediol12A. 5-Ethyl-5H-benzo[b]carbazole-6-carbaldehyde

5-Ethyl-6-methyl-5H-benzo[b]carbazole (Cambridge Chemicals, Inc.) wasformylated using the procedure of A. Rieche et al., Chem. Ber. 93, 88(1960) to give a 44.9% yield of5-ethyl-5H-benzo[b]carbazole-6-carbaldehyde, mp 95.5°-96.5°, (C,H,N),(PhCH₃).

12B.2[(5-Ethyl-5H-benzo[b]carbazol-6-yl)methy]amino]-2-methyl-1,3-propanediolmethanesulfonate

Using the procedure outlined in Example 1,5-ethyl-5H-benzo[b]carbazole-6-carbaldehyde (12A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 68.0% yield of2-[(5-ethyl-5H-benzo[b]carbazol-6-yl)methyl]amino]2-methyl-1,3-propanediolmethanesulfonate, mp 174°-175°, (C,H,N,S), (EtOH/Et₂ O).

EXAMPLE 132-[(Benzo[b]naphtho[1,2-d]thiophen-5-ylmethyl)amino]2-methyl-1,3-propanediol13A. Benzo[b]naphtho[1,2-d]thiophene-5-carbaldehyde

Benzo[b]naphtho[1,2-d]thiophene (H. G. Pars Pharmaceutical Laboratories,Inc.) was formylated using the procedure of A. Rieche et al., Chem. Ber.93, 88 (1960) to give a 49.3% yield ofbenzo[b]naphtho[1,2-d]thiophene-5-carbaldehyde, mp 142°-144°, (C,H,S),(CH₂ Cl₂ /hexane).

13B .2-[(Benzo[b]naphtho[1,2-d]thiophen-5-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate.0.5 H₂ O

Using the procedure outlined in Example 1,benzo[b]naphtho[1,2-d]thiophen-5-carbaldehyde (13A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 73.% yield of2-[(benzo[b]naphtho[1,2-d]thiophen-5-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate.0.5 H₂ O, mp 209°-209.5°, (C,H,N,S), (EtOH/Et₂ O).

EXAMPLE 142-Methyl-2-[(phenanthro[1,2-b]furan-2-ylmethyl)-amino]1,3-propanediol14A. Phenanthro[1,2-b]furan-2-methanol

To a RB flask equipped with magnetic stirring bar, reflux condenser, N₂inlet tube with bubbler was added ethylphenanthro(1,2-b]furan-2-carboxylate (H. G. Pars PharmaceuticalLaboratories, Inc., 7.9 g, 27.2 mmol), lithium borohydride (Aldrich,0.65 g, 30 mmol) and dry THF (400 mL). The mixture was stirred at refluxfor 6 h and then poured into H₂ O (1 L). The reaction mixture wasacidified with 1N HCl and the resulting white solid was filtered, washedwith additional H₂ O (1500 mL) then dissolved in CH₂ Cl₂ (500 mL), dried(Na₂ SO₄), filtered, concentrated to 200 mL and diluted to 500 mL withhexane. The resulting material was filtered, washed with hexane (100 mL)and placed in a vacuum oven overnight. A total of 6.1 g (90.1%) ofphenanthro[1,2-b]furan-2-methanol, mp 125°-126° was obtained (C,H).

14B. Phenanthro[1,2-b]furan-2 -carbaldehyde

To a RB flask equipped with magnetic stirring bar, reflux condenser, N₂inlet line with bubbler was added phenanthro[1,2-b]furan-2-methanol(14A, 5.84 g, 23.5 mmol), barium manganate (Aldrich, 12.06 g, 47 mmol)and dry CH₂ Cl₂ (400 mL). The mixture was refluxed for 6 h, filtered andthe resulting dark yellow solution filtered through a small plus of SiO₂to remove inorganic salts and polar baseline material The solvent wasthen removed by rotary evaporation and the crude material recrystallizedusing CH₂ Cl₂ /hexane to give after drying 5.17 g (91% yield) ofphenanthro[1,2-b]furan-2-carbaldehyde, mp 169°, (C,H).

14C.2-Methyl-2-[(phenanthro[1,2-b]furan-2-ylmethyl)amino]-1,3-propanediolmethanesulfonate.0.5 H₂ O

Using the procedure outlined in Example 1,phenanthro[1,2-b]furan-2-carbaldehyde (14B) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 57.1% yield of2-methyl-2-[(phenanthro[1,2-b]furan-2-ylmethyl)amino]1,3-propanediolmethanesulfonate.0.5 H₂ O, mp 168°-170° (dec), (C,H,N,S), (EtOH/Et₂ O).

EXAMPLE 152-Methyl-2-[(phenanthro[1,2-b]furan-11-ylmethyl)amino]1,3-propanediol15A. Ethyl 11-formyl-phenanthro[1,2-b]furan-2-carboxylate

Ethyl phenanthro[1,2-b]furan-2-carboxylate (H. G. Pars PharmaceuticalLaboratories, Inc.) was formylated by the procedure of A. Rieche et al.,Chem. Ber. 93, 88 (1960) to give a crude mixture of aldehydes in 54%yield which was used in the next step without purification. Ananalytical sample of the main component of this mixture, ethyl11-formylphenanthro-[1,2-b]furan-2-carboxylate, mp 209°-212° wasproduced by column chromatography followed by crystallization, (C,H),(Ch₂ Cl₂ /hexane).

15B. Phenanthro[1,2-b]furan-11-carbaldehyde

To a RB flask equipped with magnetic stirring bar condenser, and N₂inlet line with bubbler was added ethyl11-formyl-phenanthro[1,2-b]furan-2-carboxylate (15A, 2.5 g, 7.8 mmol),1N NaOH solution (25 mL), THF (50 mL) and H₂ O (25 mL). The mixture wasrefluxed for 2 h until it became homogeneous. The mixture was acidifiedwith 1N HCl and the solvent removed by rotary evaporation. The crudesolid was then heated to 150° with copper powder (0.9 g) and quinoline(Alrich, 25 mL) for 1 h. The reaction mixture was cooled and thequinoline removed under vacuum to give a crude dark green solid. Afterchromatography and crystallization (CH₂ Cl₂ /hexane) 0.71 g (37% yield)of phenanthro[1,2-b]furan-11-carbaldehyde, mp 145°-150°, (C,H).

15C.2-Methyl-2-[(phenanthro[1,2-b]furan-11-ylmethyl)amino]-1,3-propanediolmethanesulfonate

Using the procedure outlined in Example 1,phenanthro[1,2-b]furan-11-carbaldehyde (15B) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 57.6% yield of2-methyl- 2-[(phenanthro[1,2-b]furan-11-ylmethyl)-amino]1,3-propanediolmethanesulfonate, mp 186°-188° (dec), (C,H,N,S), (EtOH/Et₂ O).

EXAMPLE 162-Methyl-2-[(phenanthro[1,2-b]thiophen-2-ylmethyl)-amino]1,3-propanediol16A. Phenanthro[1,2-b]thiophene-2-methanol

Using the procedure outlined in 14A, ethylphenanthro[1,2-b]thiophene-2-carboxylate (H. G. Pars PharmaceuticalLaboratories, Inc.) gave a 98.0% yield ofphenanthro[1,2-b]thiophene-2-methanol, mp 169°-170.5° (C,H,S), (Ch₂ Cl₂/hexane).

16B. Phenanthro[1,2-b]thiophene-2-carbaldehyde

Using the procedure outlined in 14B,phenanthro[1,2-b]thiophene-2-methanol (16A) gave a 82.9% yield ofphenanthro[1,2-b ]thiophene-2-carbaldehyde, mp 209°-210°, (C,H,S), (CH₂Cl₂ /hexane).

16C.2-Methyl-2-[(phenanthro[1,2-b]thiophen-2-ylmethyl)amino]1,3-propanediolmethanesulfonate.0.6 H₂ O

Using the procedure outlined in Example 1,phenanthro[1,2-b]thiophene-2-carbaldehyde (16B) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave an 82.7% yield of2-methyl-2-[(phenanthro[1,2-b]thiophen-2-ylmethyl)amino]-1,3-propanediolmethanesulfonate.0.6 H₂ O, mp 209°-209.5° (dec), (C,H,N,S), (CH₃ OH/Et₂O).

EXAMPLE 172-Methyl-2-[(phenanthro[1,2-b]thiophen-11-ylmethyl)amino]-1,3-propanediol17A. Phenanthro[1,2-b]thiophene-11-carbaldehyde

Ethyl phenanthro[1,2-b]thiophene-2-carboxylate was formylated using theprocedure of A. Rieche et al., Chem. Ber. 93, 88 (1960), to give a lowyield of a mixture of aldehyde esters. The mixture was directlyhydrolyzed as in Example 15B and the resulting crude mixture of aldehydeacids was decarboxylated as in Example 15B to give a crude mixture ofaldehydes. The main component of the mixture,phenanthro[1,2-b]thiophene-11-carbaldehyde, mp 161.5°-162.5° wasobtained after chromatography and crystallization in 3.1% overall yield,(C,H,S), (PhCH₃).

17B.2-Methyl-2-[(phenanthro[1,2-b]thiophen-11-ylmethyl)amino]-1,3-propanediolmethanesulfonate

Using the procedure outlined in Example 1,phenanthro[1,2-b]-thiophene-11-carbaldehyde (17A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 56.5% yield of2-methyl-2-[(phenanthro[1,2-b]thiophen-11-ylmethyl)amino]-1,3-propanediolmethanesulfonate, mp 206°-207° (dec), (C,H,N,S), (EtOH/Et₂ O).

EXAMPLE 182-Methyl-2-[(phenanthro[4,3-b]furan-2-ylmethyl)amino]1,3-propanediol18A. Phenanthro[4,3-b]furan-2-methanol

Using the procedure outlined in Example 14A, ethylphenanthro[4,3-b]furan-2-carboxylate (H. G. Pars PharmaceuticalLaboratories, Inc.) gave a 91% yield ofphenanthro[4,3-b]furan-2-methanol, mp 125°-126°, (C,H), (CH₂ Cl₂/hexane).

18B. Phenanthro[4,3-b]furan-2-carbaldehyde

Using the procedure outlined in Example 14B,phenanthro[4,3-b]furan-2-methanol (18A) gave a 91.2% yield ofphenanthro[4,3-b]furan-2-carbaldehyde, mp 169°, (C,H), (95% EtOH/CH₂Cl₂).

18C.2-Methyl-2-[(phenanthro[4,3-b]furan-2-ylmethyl)amino]1,3-propanediolmethanesulfonate

Using the procedure outlined in Example 1,phenanthro[4,3-b]furan-2-carbaldehyde (18B) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 56.5% yield of2-methyl-2-[(phenanthro[4,3-b]furan-2-ylmethyl)amino]1,3-propanediolmethanesulfonate, mp 186°-188° (dec), (C,H,N,S), (EtOH/Et₂ O).

EXAMPLE 19 2-Methyl-2-[(phenanthro[4,3-b]thiophen-7-ylmethyl)amino]1,3-propanediol 19A. Phenanthro[4,3-b]thiophene-7-carbaldehyde

Using the procedure outlined in Example 17A ethylphenanthro[4,3-b]thiophene-2-carboxylate (H. G. Pars PharmaceuticalLaboratories, Inc.) gave a 6.7% yield ofphenanthro[4,3-b]thiophene-7-carbaldehyde, mp 173°-177° (C,H,S),(PhCH₃).

19B.2-Methyl-2-[(phenanthro[4,3-b]thiophen-7-ylmethyl)amino]-1,3-propanediolmethanesulfonate.0.25 H₂ O

Using the procedure outlined in Example 1,phenanthro[4,3-b]thiophene-7-carbaldehyde (19A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 53.8% yield of2-methyl-2-[(phenanthro[4,3-b]thiophen-7-ylmethyl)amino]-1,3-propanediolmethanesulfonate.0.25 H₂ O, mp 189°-191° (dec), (C,H,N,S), (EtOH/Et₂ O).

EXAMPLE 202-Methyl-2-[(phenanthro[9,10-b]furan-2-ylmethyl)amino]1,3-propanediol20A. Phenanthro[9,10-b]furan-2-carbaldehyde

Phenanthro[9,10-b]furan (prepared by the procedure of P. Muller and J.Pfyffer, Chimia 38, 79 (1984)) was formylated using the procedure of A.Rieche et al., Chem. Ber. 93, 88 (1960) to give a 32.8% yield ofphenanthro[9,10-b]furan-2-carbaldehyde, mp 84°-85°, (C,H), (PhCH₃).

20B.2-Methyl-2-[(phenanthro[9,10-b]furan-2-ylmethyl)amino]1,3-propanediolmethanesulfonate.0.2 H₂ O.0.2 EtOH

Using the procedure outlined in Example 1,phenanthro[9,10-b]furan-2-carbaldehyde (20A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 39% yield of2-methyl-2-[(phenanthro[9,10-b]furan-2-ylmethyl)amino]1,3-propanediolmethanesulfonate.0.2 H₂ O0.2 EtOH, mp 218°-219° (dec), (C,H,N,S),(EtOH/Et₂ O).

EXAMPLE 212-Methyl-2-[(phenanthro[9,10-c]thiophen-1-ylmethyl)amino]-1,3-propanediol21A. Phenanthro[9,10-c]thiophene-1-carbaldehyde

Phenanthro[9,10-c]thiophene (H. G. Pars Pharmaceutical Laboratories,Inc.) was formylated using the procedure of A. Rieche et al., Chem. Ber.93, 88 (1960) to give a 85.9% yield ofphenanthro]9,10-c]thiophene-1-carbaldehyde, mp 198°-199°, (C,H,S),(THF/95% EtOH).

21B.2-Methyl-2-[(phenanthro[9,10-c]thiophen-1-ylmethyl)amino]-1,3-propanediolmethanesulfonate.0.25 H₂ O

Using the procedure outlined in Example 1,phenanthro[9,10-c]-thiophene-1-carbaldehyde (21A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 39.2% yield of2-methyl-2-[(phenanthro[9,10-c]thiophen-1-ylmethyl)amino]-1,3-propanediolmethanesulfonate.0.25 H₂ O, mp 180°-187° (dec), (C,H,N,S), (EtOH/Et₂ O).

EXAMPLE 222-[Acenaphtho-[1,2-b]-thiophen-8-ylmethyl)amino]-2-methyl-1,3-propanediolhydrochloride

Using the procedure outlined in Example 1,acenaphtho[1,2-b]thiophene-8-carbaldehyde (H. G. Pars PharmaceuticalLaboratories, Inc.) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gavea 73.8% yield of2-[8-acenaphtho-[1,2-b]thiophen-8-ylmethyl)amino]-2-methyl-1,3-propanediolhydrochloride, mp 208°-210° (dec), (C,H,N,Cl,S), (EtOH/Et₂ O).

EXAMPLE 232-[Acenaphtho-[1,2-c]-thiophen-7-ylmethyl)amino]-2-methyl-1,3-propanediol23A. Acenaphtho[1,2-c]thiophene-7-carbaldehyde

Acenaphtho[1,2-c]thiophene (H. G. Pars Pharmaceutical Laboratories,Inc.) was formylated according to the procedure of A. Rieche et al.,Chem. Ber. 93, 88 (1960) to give an 83.2% yield ofacenaphtho[1,2-c]thiophene-7-carbaldehyde, mp 123°-125.5°, (C,H,S).

23B.2-[Acenaphtho-[1,2-c]thiophen-7-ylmethyl)amino]-2-methyl-1,3-propanediolhydrochloride

Using the procedure outlined in Example 1,acenaphtho[1,2-c]-thiophene-7-carbaldehyde (23A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 57.4% yield of2-[(acenaphtho-[1,2-c]thiophen-7-ylmethyl)amino]2-methyl-1,3-propanediolhydrochloride, mp 220°-223° (dec), (C,H,N,Cl,S), (EtOH/Et₂ O).

Antitumor Screening Results

Methods for evaluating the antitumor activity of these compounds areessentially those used in the Tumor Panel by the DevelopmentTherapeutics Program, Division of Cancer Treatment, National CancerInstitute, A. Goldin, et al., Methods in Cancer Research, Vol. XVI, p.165, Academic Press (1979). Some modifications, in dose level andschedule have been made to increase the testing efficiency.

EXAMPLE 24 Lymphocytic Leukemia P388/0 Test

CD2-F₁ mice, of the same sex, weighing 20±3 g, are used for this test.Control and test animals are injected intrapertioneally with asuspension of -10⁶ viable P388/0 tumor cells on day 0. In each test,several dose levels which bracket the LD₂₀ of the compound areevaluated; each dose level group contains six animals. The testcompounds are prepared either in physiologic saline containing 0.05%Tween 80 or distilled water containing 5% dextrose and are administeredintrapertioneally on days 1, 5, and 9 relative to tumor implant. Dosesare on a mg/kg basis according to individual animals' body weights. Theday of death for each animal is recorded, the median identified for eachgroup and the ratios of median survival time for treated (T)/control (C)groups are calculated. The criterion for activity is T/C×100≧120%.Results of P388/0 testing are summarized in Table I.

                  TABLE I                                                         ______________________________________                                                Optimal  T/C × 100%                                                                            30 Day                                         Compound                                                                              Dose     (Excluding 30 Day)                                                                          Sur-   LD.sub.20                               of Formula                                                                            (mg/kg)  Survivors     vivors (mg/kg)                                 ______________________________________                                        1       65       +225          0/6    35                                      2B      100      +250          1/6    50                                      3B      20       +230          2/6    10                                      4D      80       >+300         6/6    55                                      5B      125      +255          4/6    100                                     6B      65       +210          0/6    35                                      7B      450      +158          0/6    400                                     9B      110      +205          0/6    140                                     10      400      +290          2/5    320                                     12B     175      +140          0/6    200                                     13B     20       +155          0/6    20                                      15C     120      +227          1/6    120                                     17B     120      +223          0/6    120                                     19B     2.5      +145          0/6    1.0                                     20B     175      +167          0/6    175                                     21B     320      +140          0/6    320                                     23B     350      +120          0/6    300                                     ______________________________________                                    

EXAMPLE 25 Formulation Examples

    ______________________________________                                        A. TABLET                                                                     ______________________________________                                        Compound of Formula I   500.0  mg                                             Pregelatinized Corn Starch                                                                            60.0   mg                                             Sodium Starch Glycolate 36.0   mg                                             Magnesium Stearate      4.0    mg                                             ______________________________________                                    

The compound of formula (I) is finely ground and intimately mixed withthe powdered excipients, pregelatinized corn starch and sodium starchglycolate. The powders are wetted with purified water to form granules.The granules are dried and mixed with the magnesium stearate. Theformulation is then compressed into tablets weighing approximately 600mg each.

    ______________________________________                                        B. TABLET                                                                     ______________________________________                                        Compound of formula (I) 500.0  mg                                             Corn Starch             70.0   mg                                             Lactose                 83.8   mg                                             Magnesium Stearate      4.2    mg                                             Polyvinylpyrrolidone    14.0   mg                                             Stearic Acid            28.0   mg                                             ______________________________________                                    

The compound of formula (I) is finely ground and intimately mixed withthe powdered excipients, corn starch and lactose. The powders are wettedwith a solution of polyvinylpyrrolidone dissolved in a mixture ofpurified water and denatured alcohol to form granules. The granules aredried and mixed with the powdered stearic acid and magnesium stearate.The formulation is then compressed into tablets weighing approximately700 mg each.

    ______________________________________                                        C. CAPSULES                                                                   ______________________________________                                        Compound of formula (I) 500.0  mg                                             Corn Starch             50.0   mg                                             Magnesium Stearate      3.0    mg                                             ______________________________________                                    

The finely divided compound of formula (I) is mixed with powdered cornstarch and wetted with denatured alcohol to densify the powder. Thedried powder is mixed with stearic acid and filled into hard-shellgelatin capsules.

    ______________________________________                                        D. SYRUP                                                                      ______________________________________                                        Compound of formula (I)      250.0 mg                                         Ethanol                      250.0 mg                                         Glycerin                     500.0 mg                                         Sucrose                      3,500.0 mg                                       Flavoring Agent              q.s.                                             Coloring Agent               q.s.                                             Preserving Agent             0.1%                                             Purified Water     q.s. to   5.0 mL                                           ______________________________________                                    

The compound of formula (I) is dissolved in the ethanol, glycerin, and aportion of the purified water. The sucrose and preserving agent aredissolved in another portion of hot purified water, and then thecoloring agent is added and dissolved. The two solutions are mixed andcooled before the flavoring agent is added. Purified water is added tofinal volume. The resulting syrup is throughly mixed.

    ______________________________________                                        E. IV INJECTION                                                               ______________________________________                                        Compound of formula (I)                                                                            5.0 mg                                                   Glycerin             q.s. for isotonicity                                     Preservative         0.1%                                                     Hydrochloric Acid or as needed for                                            Sodium Hydroxide     pH adjustment                                            Water for Injection  q.s. to mL                                               ______________________________________                                    

The compound of formula (I) and preservative is added to the glycerinand a portion of the water for injection. The pH is adjusted withhydrochloric acid or sodium hydroxide. Water for injection is added tofinal volume and solution is complete after thorough mixing. Thesolution is sterilized by filtration through a 0.22 micrometer membranefilter and aseptically filled into sterile 10 mL ampules or vials.

What is claimed is:
 1. A compound of formula (I)

    ArCH.sub.2 R.sup.1                                         (I)

and acid addition salts thereof; wherein Ar is a fused tetrayclic aromatic phenanthro[9, 10-b] furan or phenanthro [9, 10-c] furan ring system optionally substituted by one or two substituents, the substituents will contain not more than four carbon atoms in total when taken together being the same or different and are selected from halogen; cyano; C₁₋₄ alkyl or C₁₋₄ alkoxy, each optionally substituted by hydroxy or C₁₋₂ alkoxy; halogen substituted C₁₋₂ alkyl or C₁₋₂ alkoxy; a group S(O)_(n) R² wherein n is an integer 0, 1 or 2 and R² is C₁₋₂ alkyl optionally substituted by hydroxy or C₁₋₂ alkoxy; or the heterocyclic ring is optionally substituted by a group NR³ R⁴ containing not more than carbon atoms wherein R³ and R⁴ are the same or different and each is a C₁₋₃ alkyl group; R¹ contains not more than eight carbon atoms and is a group ##STR14## wherein m is 0 or 1; R⁵ is hydrogen; R⁶ and R⁷ are the same or different and each is hydrogen or C₁₋₅ alkyl optionally substituted by hydroxy; R⁸ and R⁹ are the same or different and each is hydrogen or C₁₋₃ alkyl; --C--C-- is a five- or six-membered saturated carbocyclic ring; R¹⁰ is hydrogen, methyl or hydroxymethyl; R¹¹, R¹² and R¹³ are the same or different and each is hydrogen or methyl; R¹⁴ is hydrogen, methyl, hydroxy, or hydroxymethyl.
 2. A compound of claim 1 wherein Ar is ##STR15## wherein Z is 0.R¹ is ##STR16## wherein m is 0; R¹⁶ is Ch₂ OH, Ch(CH₃)OH or CH₂ CH₂ OH; R¹⁷ is hydrogen, C₁₋₃ alkyl or CH₂ OH; R¹⁸ is hydrogen or methyl.
 3. A compound of claim 1 as an acid addition salt of hydrochloric, methanesulfonic, ethanesulfonic, lactic, citric or isethionic acid.
 4. A compound of claim 1 which is 2-methyl-2-[(phenanthro[9,10-b]furan-2-ylmethyl)amino]-1,3-propanediol or a pharmaceutically acceptable acid addition salt thereof.
 5. A compound of claim 4 as an acid addition salt of hydrochloric, ethanesulfonic, lactic, citric or isethionic acid.
 6. 2-Methyl-2-[(phenanthro[9,10-b]furan-2-ylmethyl)amino]-1,3-propanediol methanesulfonate.
 7. A method for reducing the number of cells of a solid or ascitic tumor susceptible to such reduction in a mammal bearing said tumor comprising the administration of an effective tumor cell number reducing amount of a compound of formula (I)

    ArCH.sub.2 R.sup.1                                         (I)

and acid addition salts thereof; wherein is a fused tetracyclic aromatic phenanthro [9, 10-b] furan or phenanthro [9, 10-c] furan ring system optionally substituted by one or two substituents, the substituents will contain not more then four carbon atoms in total when taken together being the same or different and are selected from halogen; cyano; C₁₋₄ alkyl or C₁₋₄ alkoxy, each optionally substituted by hydroxy or C₁₋₂ alkoxy; halogen substituted C₁₋₂ alkyl or C₁₋₂ alkoxy; a group S(O)_(n) R² wherein n is an integer 0, 1 or 2 and R² is C₁₋₂ alkyl optionally substituted by hydroxy or C₁₋₂ alkoxy; or the heterocyclic ring is optionally substituted by a group NR³ R⁴ containing not more than 5 carbon atoms wherein R³ and R⁴ are the same or different and each is a C₁₋₃ alkyl group; R¹ contains not more than eight carbon atoms and is a group ##STR17## wherein m is 0 or 1; R⁵ is hydrogen; R⁶ and R⁷ are the same or different and each is hydrogen or C₁₋₅ alkyl optionally substituted by hydroxy; R⁸ and R⁹ are the same or different and each is hydrogen or C₁₋₃ alkyl; --C--C-- is a five- or six-membered saturated carbocyclic ring; R¹⁰ is hydrogen, methyl or hydroxymethyl; R¹¹, R¹² and R¹³ are the same or different and each is hydrogen or methyl; R¹⁴ is hydrogen; methyl, hydroxy, or hydroxymethyl.
 8. A method of claim 7 wherein Ar is ##STR18## wherein Z is 0;R¹ is ##STR19## R¹⁶ is CH₂ OH, CH(CH₃)OH or CH₂ CH₂ OH; R¹⁷ is hydrogen, C₁₋₃ alkyl or CH₂ OH; R¹⁸ is hydrogen or methyl.
 9. A method for reducing the number of cells of a solid or ascitic tumor susceptible to such reduction or prevention of growth in the mammal bearing said tumor comprising the administration of 2-methyl-2-[(phenanthro[9,10-b]furan-2-ylmethyl)amino]-1,3-propanediol or a pharmaceutically acceptable acid addition salt thereof.
 10. A method of claim 9 wherein the compound is 2-methyl-2-[(phenanthro[9,10-b]furan-2-ylmethyl)amino]-1,3-propanediol methanesulfonate.
 11. A pharmaceutical formulation containing a compound of formula (I)

    ArCH.sub.2 R.sup.1                                         (I)

and acid addition salts thereof; wherein Ar is a fused tetracyclic aromatic phenanthro [9, 10-b] furan or phenanthro [9,10-c] furan ring system optionally substituted by one or two substituents, the substituents will contain not more than four carbon atoms in total when taken together being the same or different and are selected from halogen; cyano; C₁₋₄ alkyl or C₁₋₄ alkoxy, each optionally substituted by hydroxy or C₁₋₂ alkoxy; halogen substituted C₁₋₂ alkyl or C₁₋₂ alkoxy; a group S(O)_(n) R² wherein n is an integer 0, 1 or 2 and R² is C₁₋₂ alkyl optionally substituted by hydroxy or C₁₋₂ alkoxy; or the heterocyclic ring is optionally substituted by a group NR³ R⁴ containing not more than 5 carbon atoms wherein R³ and R⁴ are the same or different and each is a C₁₋₃ alkyl group; R¹ contains not more than eight carbon atoms and is a group ##STR20## wherein m is 0 or 1; R⁵ is hydrogen; R⁶ and R⁷ are the same or different and each is hydrogen or C₁₋₅ alkyl optionally substituted by hydroxy; R⁸ and R⁹ are the same or different and each is hydrogen or C₁₋₃ alkyl; --C--C-- is a five- or six-membered saturated carbocyclic ring; R¹⁰ is hydrogen, methyl or hydroxymethyl; R¹¹, R¹² and R¹³ are the same or different and each is hydrogen or methyl; R¹⁴ is hydrogen, methyl, hydroxy, or hydroxymethyl with a pharmaceutically acceptable carrier in the form of a tablet, capsule, syrup, or injection.
 12. A pharmaceutical formulation of claim 11 wherein Ar is ##STR21## wherein Z is O;R¹ is ##STR22## R¹⁶ is CH₂ OH, CH(CH₃)OH or CH₂ CH₂ OH; R¹⁷ is hydrogen, C₁₋₃ alkyl or CH₂ OH; R¹⁸ is hydrogen or methyl.
 13. A pharmaceutical formulation of claim 11 in the form of an injection.
 14. A pharmaceutical formulation of claim 11 in the form of an injection. 